*Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158; and Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark–Odense University, DK-5230 Odense M, Denmark
Communicated by C. David Allis, The Rockefeller University, New York, NY, May 12, 2006 (received for review April 8, 2006)
We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.
sir2 | SIRT3 | SIRT5 | sirtuin
Conflict of interest statement: No conflicts declared.
To whom correspondence should be addressed. E-mail: everdin{at}gladstone.ucsf.edu
© 2006 by The National Academy of Sciences of the USA
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